Over 10% of Americans suffer from chronic sleep disorders, with an estimated annual cost of $100 billion. Drug and alcohol addiction severely disrupt sleep, and sleep disorders increase the risk of addiction and relapse. Understanding the mechanisms that regulate sleep is thus critical for preventing and treating addiction. Furthermore, most drugs used to treat insomnia, the most common sleep disorder, act by inhibiting GABA receptors, which are relatively non-specific targets for sleep. These drugs only ameliorate some symptoms and are often addictive. Thus, new drugs that target more specific sleep regulators are needed. We recently established zebrafish as a vertebrate system for studying the genetic and neural mechanisms that regulate sleep. Zebrafish are a useful model for these studies because they have the basic brain structures and genes that are thought to regulate mammalian sleep, but are also optically transparent and amenable to high- throughput screens and behavior assays. This proposal has four specific aims. First, we will use genetic and pharmacological approaches to determine which adenosine receptors regulate zebrafish sleep/wake states. Second, we will determine which neural substrates are used by adenosine to regulate zebrafish sleep. Third, we will test the hypothesis that adenosine promotes sleep by inhibiting the Hypocretin system. Fourth, we will test the hypothesis that adenosine regulates sleep by modulating the activities of other sleep regulatory systems. These experiments will clarify how adenosine regulates sleep, which may provide clues to the basis of sleep disorders and suggest novel therapies for sleep disorders and addiction. PUBLIC HEALTH RELEVANCE: Drug and alcohol addiction severely disrupt sleep, and sleep disorders increase the risk of addiction and relapse. Understanding the mechanisms that regulate sleep is thus critical for preventing and treating addiction. This proposal will use zebrafish to determine the genetic and neurological mechanisms through which adenosine regulates sleep. The proposed studies will improve understanding of the genetic and neuronal mechanisms that regulate sleep and may suggest new strategies to treat sleep and addiction disorders.